The benefits and risks of menopause hormone therapy for the cardiovascular system in postmenopausal women: a systematic review and meta-analysis

Background Menopause hormone therapy (MHT), as an effective method to alleviate the menopause-related symptoms of women, its benefits, risks, and potential influencing factors for the cardiovascular system of postmenopausal women are not very clear. Objectives To evaluate cardiovascular benefits and risks of MHT in postmenopausal women, and analyze the underlying factors that affect both. Search strategy The EMBASE, MEDLINE, and CENTRAL databases were searched from 1975 to July 2022. Selection criteria Randomized Clinical Trials (RCTs) that met pre-specified inclusion criteria were included. Data collection and analysis Two reviewers extracted data independently. A meta-analysis of random effects was used to analyze data. Main results This systematic review identified 33 RCTs using MHT involving 44,639 postmenopausal women with a mean age of 60.3 (range 48 to 72 years). There was no significant difference between MHT and placebo (or no treatment) in all-cause death (RR = 0.96, 95%CI 0.85 to 1.09, I2 = 14%) and cardiovascular events (RR = 0.97, 95%CI 0.82 to 1.14, I2 = 38%) in the overall population of postmenopausal women. However, MHT would increase the risk of stroke (RR = 1.23, 95%CI 1.08 to 1.41,I2 = 0%) and venous thromboembolism (RR = 1.86, 95%CI 1.39 to 2.50, I2 = 24%). Compared with placebo, MHT could improve flow-mediated arterial dilation (FMD) (SMD = 1.46, 95%CI 0.86 to 2.07, I2 = 90%), but it did not improve nitroglycerin-mediated arterial dilation (NMD) (SMD = 0.27, 95%CI − 0.08 to 0.62, I2 = 76%). Compared with women started MHT more than 10 years after menopause, women started MHT within 10 years after menopause had lower frequency of all-cause death (P = 0.02) and cardiovascular events (P = 0.002), and more significant improvement in FMD (P = 0.0003). Compared to mono-estrogen therapy, the combination therapy of estrogen and progesterone would not alter the outcomes of endpoint event. (all-cause death P = 0.52, cardiovascular events P = 0.90, stroke P = 0.85, venous thromboembolism P = 0.33, FMD P = 0.46, NMD P = 0.27). Conclusions MHT improves flow-mediated arterial dilation (FMD) but fails to lower the risk of all-cause death and cardiovascular events, and increases the risk of stroke and venous thrombosis in postmenopausal women. Early acceptance of MHT not only reduces the risk of all-cause death and cardiovascular events but also further improves FMD, although the risk of stroke and venous thrombosis is not reduced. There is no difference in the outcome of cardiovascular system endpoints between mono-estrogen therapy and combination therapy of estrogen and progesterone. Supplementary Information The online version contains supplementary material available at 10.1186/s12905-023-02788-0.


Supplementary Materials
The Benefits and Risks of Menopause Hormone Therapy for the Cardiovascular System in Postmenopausal Women:

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Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.6 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.

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Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.sMethods.1 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Section and Topic Item # Checklist item Location where item is reported

Data items
List and define all other variables for which data were sought (e.g.participant and intervention characteristics).
Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Synthesis methods Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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Reporting bias assessment Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).8 Certainty assessment Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.8

Study selection
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

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Study characteristics Cite each included study and present its characteristics.9,Table1 Risk of bias in studies Present assessments of risk of bias for each included study.10,sFigure1 Results of individual studies 10-14, For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.3

Results of syntheses
Present results of all investigations of possible causes of heterogeneity among study results.14-15, sFigure2,4 Reporting biases Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.14-15, sFigure1,3

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Figure S1 Evaluate the bias risk of trials included in the systematic review based on the bias risk assessment criteria in Cochrane Handbook for Systematic Reviews of Interventions Figure S2 Sensitivity Analysis (leave one-out method) Figure S3 Funnel plots Figure S4 Subgroup analysis of different MHT treatment durations Figure S5 Subgroup analysis of MHT onset time Figure S6 Subgroup analysis of primary prevention and secondary prevention of MHT Figure S7 Subgroup analysis of MHT protocols

Figure S4A :FigureFigure S5A :Figure S5C :FigureFigure S6A :FigureFigure S7A :
Figure S1 Evaluate the bias risk of trials included in the systematic review based on the bias risk assessment criteria in Cochrane Handbook for Systematic Reviews of Interventions

Table S1 Evaluation of evidence quality based on GRADE approach
CI: confidence interval; RR: risk ratio; SMD: standardized mean difference.Explanations a. Could be imprecise due to I2=90%, Although a large number of clinical trials have proved its strong correlation.Nevertheless,we conservatively rated down for imprecision.b.Could be imprecise due to I2=76%, we conservatively rated down for imprecision

Table S2 PRISMA checklist
Objectives4 Provide an explicit statement of the subject(s), intervention(s),outcome(s) and study design the review addresses.4-5METHODSProtocolandregistrationIndicate if a review protocol exists, if and where it can be accessed, if available, provide registration information such as registration number.